Abstract
Our previous study observed that circular RNA protein tyrosine kinase 2 (circ-PTK2) was upregulated and correlated with worse clinical features and unfavorable prognosis in multiple myeloma (MM) patients. Thus, this study aimed to further characterize the regulatory function of circ-PTK2 on cell malignant activities and its target microRNA-638 (miR-638) as well as downstream MEK/ERK, WNT/β-catenin signaling pathways in MM. The effect of circ-PTK2 on MM cell proliferation, apoptosis, migration, invasion and its potential target miRNAs was assessed by transfecting circ-PTK2 overexpression plasmids into U226 cells and circ-PTK2 knock-down plasmids into LP-1 cells. Furthermore, the interaction between circ-PTK2 and miR-638 mediated MEK/ERK and WNT/β-catenin signaling pathways was validated by rescue experiments. Circ-PTK2 was overexpressed in most MM cell lines compared to normal plasma cells. Overexpressing circ-PTK2 promoted proliferation and migration, inhibited apoptosis in U266 cells, but did not affect cell invasion; knocking down circ-PTK2 achieved opposite effect in LP-1 cells. Besides, circ-PTK2 reversely regulated miR-638 expression but not miR-4690, miR-6724, miR-6749 or miR-6775. The following luciferase reporter assay illustrated the direct bind of circ-PTK2 towards miR-638. In rescue experiments, overexpressing miR-638 suppressed proliferation, migration, while promoted apoptosis in both wild U266 cells and circ-PTK2-overexpressed U266 cells; meanwhile, overexpressing miR-638 also suppressed MEK/ERK and WNT/β-catenin pathways in both wild U266 cells and circ-PTK2-overexpressed U266 cells. Knocking down miR-638 achieved opposite effect in both wild LP-1 cells and circ-PTK2-knocked-down LP-1 cells. In conclusion, circ-PTK2 promotes cell proliferation, migration, suppresses cell apoptosis via miR-638 mediated MEK&ERK and WNT&β-catenin signaling pathways in MM.
Highlights
Multiple myeloma is a bone marrow-originated plasma cell malignancy that accounts for about 13% of hematological malignancies [1, 2]
As to determine whether circ-PTK2 was dysregulated in MM cell lines, reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed, which observed that expression of Circ-PTK2 was upregulated in NCI-H929 (P
Since the lowest circ-PTK2 expression was observed in U266 cell, it was chosen for circ-PTK2 overexpression experiments
Summary
Multiple myeloma is a bone marrow-originated plasma cell malignancy that accounts for about 13% of hematological malignancies [1, 2]. As the mainstay of MM treatment in the early 2000s, chemotherapy in combination with steroids realize a median survival of 3-5 years, whereas with the development of new agents including novel targeted therapies, immunomodulatory drugs and stem cell transplantation during the past 15 years, the median survival has increased to 7-8 years [2]. What’s more, drug resistance as well as treatment-related toxicity are risk factors hindering the prognosis of MM patients [1]. Researches are dedicating to exploring biological characteristics and pathogenesis of MM, as well as identifying additional new regimens with help from cutting edge molecular technologies
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